Acute kidney injury (AKI) complicates the dosing strategies of oxaliplatin (L-OHP) and the requirement for L-OHP dose reduction in patients with renal failure remains controversial. The objective of this study is to assess the impact of AKI on the pharmacokinetics (PK) of intact L-OHP and simulate the relationship between the degree of renal function and intact L-OHP exposures using a population PK model. Intact L-OHP concentrations in plasma and urine after L-OHP administration were measured in mild and severe AKI models established in rats through renal ischemia-reperfusion. Population PK modeling and simulation were performed. There were no differences among rats in the area under the plasma concentration-time curve of intact L-OHP after intravenous L-OHP administrations. Nevertheless, the amount of L-OHP excretion after administration of 8 mg/kg L-OHP in mild and severe renal dysfunction rats was 63.5% and 37.7%, respectively, and strong correlations were observed between biochemical renal function markers and clearance of intact L-OHP. The population PK model simulated well the observed levels of intact L-OHP in AKI model rats. The population PK model-based simulation suggests that dose reduction is unnecessary for patients with mild to moderate AKI.
Keywords: cancer chemotherapy; pharmacokinetic modeling and simulation; platinum compounds; renal dysfunction.